Project Summary The small vessel diseases of the brain are responsible not only for ischemic and hemorrhagic strokes but also vascular cognitive impairment and dementia, major sources of disability and death in older adults. Despite the fact that hypertensive cerebral small vessel disease (HTN-cSVD) is the most common type of brain microangiopathy, the mechanisms linking this condition to brain tissue injury and cognitive impairment are unknown, therefore no specific preventive or therapeutic method targeting physiopathological processes exist. We propose a systematic, multidisciplinary analysis of the mechanisms underlying HTN-cSVD related cerebrovascular dysfunction, impaired perivascular clearance and their connections to brain damage including pathological amyloid/tau protein accumulations. The unique patient cohort is composed of nondemented survivors of a hypertensive intracerebral hemorrhage (HTN-ICH), a well-characterized indicator of severe HTN- cSVD. Specific experiments are designed to compare advanced physiological MRI measures of vascular reactivity and vascular compliance between patients with HTN-ICH and healthy older adults in addition to delineating the relationship of vascular dysfunction with established markers of HTN-cSVD [Specific Aim (SA) 1a and 1b]. These experiments are geared towards testing the hypothesis that HTN-cSVD causes vascular dysfunction which in turn might mediate larger-scale brain tissue injury. The second set of experiments will test the potential effects of HTN-cSVD on accumulation of amyloid and tau proteins in the brain, answering the key question of whether decreased clearance related to small vessel dysfunction might contribute to the accumulation of these pathological hallmarks of Alzheimer?s Disease (SA 2a and 2b). The third set of studies will analyze the effects of vascular, structural and molecular changes on cognition using both cross-sectional and longitudinal assessments (SA 3a and 3b). The proposal builds on a wide range of cutting-edge methodologic advances such as multimodal physiological imaging with 7T ultrahigh field functional MRI, molecular A and tau PET imaging, and the use of state-of-the-art structural imaging markers of HTN-cSVD. Successful completion of the proposed highly translational experiments will determine the physiological and molecular mechanisms of brain tissue damage related to HTN-cSVD and the impact of these processes on cognition. These results will represent a major step towards understanding the contributions of the most common vascular brain disease (HTN-cSVD) to dementia, thereby allowing design of clinical trials aimed at preserving or enhancing vascular function using validated imaging markers of the vascular physiology.